We recently found that animals made dependent on morphine exhibit increased drug preference 5 weeks after withdrawal. These results reveal that prior prolonged drug exposure and withdrawal alters behavioral and neural responsivity to subsequent drug administration for a substantial period of time. This observation establishes a simple behavioral model of the well-established clinical observation that former addicts have a high liability for future relapse. Our goal is to identify the neural changes that underlie this long-term alteration of drug responsivity. We hypothesize that this increased drug preference after prior exposure and withdrawal is due at least in part to changes in pathways converging on the ventrolateral bed nucleus of the stria terminalis (vBNST). In particular, we hypothesize that norepinephrine innervation of the vBNST from the A2 neurons in the nucleus tractus solitarius, or corticotropin releasing hormone inputs from the amygdala or intrinsic BNST neurons, plays a role in potentiating activity of the vBNST in response to drug-associated stimuli. We recently found an excitatory amino acid pathway from the vBNST to the ventral tegmental area; this projection strongly activates dopaminergic neurons and may therefore play a pivotal role in expression of the enhanced drug preference. We propose a set of coordinated anatomical, neurophysiological and behavioral experiments to test these hypotheses. Results of these studies will provide important new insights into neural mechanisms underlying conditioned drug seeking and relapse in abstinent addicts, a major 3roblem in treatment and prolonged abstinence.